As the prevalence of late-onset Alzheimer?s disease continues to increase, understanding the mechanistic causes of this disease is becoming increasingly critical. Recent clinical studies have linked increased stiffness of the large arteries to both impaired memory and Alzheimer?s disease. It is hypothesized that these relations are a result of large artery stiffness-induced cerebrovascular dysfunction. Increased large artery stiffness leads to greater pulsatility of pressure and blood flow in the cerebral vasculature, which is known to cause vascular damage. Dysfunction of the cerebral arteries and microvasculature is associated with cognitive impairment and greater Alzheimer?s disease-related neuropathology. Furthermore, amyloid-? (A?) induces cerebrovascular damage, and cerebrovascular impairment increases A? accumulation, thus creating a vicious cycle of cerebrovascular dysfunction and neuropathology. The goal of the proposed studies is to provide the first proof- of-concept evidence that age-related increases in large artery stiffness, synergistically with greater A? production, lead to cognitive impairment, neuropathology, and cerebrovascular dysfunction. To accomplish this goal, we will employ transgenic mouse models of greater large artery stiffness and greater A? production, as well as use a pharmacological intervention to prevent age-related increases in large artery stiffness.
In Aim 1, we will assess the effects of large artery stiffness, in combination with A?, on cognitive dysfunction and Alzheimer?s disease-related neuropathology.
In Aim 2, we will determine the effect of large artery stiffness, in combination with A?, on cerebral blood flow and cerebral vascular reactivity and structural integrity.
In Aim 3, we will identify candidate mechanisms by which large artery stiffness and greater cerebral artery pulsatility lead to cerebrovascular dysfunction. To do so, we will examine the role and source(s) of vascular oxidative stress, as well as perform transcriptome analysis of cerebral arteries and microvascular endothelial cells. The knowledge to be gained by completing the proposed aims will inform future studies to identify novel therapeutic targets for the prevention or attenuation of late-onset Alzheimer?s disease.

Public Health Relevance

With aging, there is increased stiffness of the large arteries (i.e., the aorta and carotid arteries) and stiffer large arteries are associated with Alzheimer?s disease and problems with memory. The proposed studies will determine, for the first time, the cause-and-effect relation between large artery stiffness and impairments in the brain. The knowledge gained from these studies will help identify new methods to prevent or treat Alzheimer?s disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG064016-01A1
Application #
9973881
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Mackiewicz, Miroslaw
Project Start
2020-04-15
Project End
2025-02-28
Budget Start
2020-04-15
Budget End
2021-02-28
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Oregon
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
City
Eugene
State
OR
Country
United States
Zip Code
97403